Megakaryocytic TGFβ1 orchestrates osteogenesis of LepR+ SSCs to alleviate radiation-induced bone loss

Abstract It has been reported that a close relationship exists between the hematopoietic and skeletal systems, and megakaryocytes (MKs) may play a role in maintaining bone homeostasis. However, the precise role and underlying mechanisms of MKs in osteogenesis, particularly under stress conditions, remain largely unknown. Here we demonstrate that deficiency of MKs significantly impairs bone formation, accompanied by a reduction in the number of leptin receptor positive skeletal stem cells (LepR + SSCs) in MKs conditionally deleted mice. Further investigations reveal that megakaryocytic TGFβ1 promotes the osteogenic differentiation of LepR + SSCs following irradiation. Notably, thrombopoietin treatment effectively maintains the number of LepR + SSCs and stimulates bone formation. Moreover, MKs-derived TGFβ1 facilitates zinc ions influx into LepR + SSCs by activating Slc39a14, thereby alleviating endoplasmic reticulum stress after irradiation. In addition, the increased intracellular zinc levels inhibit PTP1B expression and activate Stat3 signaling, promoting osteogenic lineage commitment. In conclusion, our findings demonstrate that the megakaryocytic TGFβ1 orchestrates the osteogenesis of LepR + SSCs following irradiation, offering a potential therapeutic strategy for radiation-induced bone loss.